Candida albicans is the major fungal pathogen of humans, and is a significant cause of morbidity and mortality especially in immunocompromised hosts. Unlike most pathogens, C. albicans is capable of infecting virtually every anatomical site within the body and has no known reservoir outside of warm-blooded animals. The ability to reversibly switch between the unicellular (yeast) and filamentous form contributes significantly to the invasion and pathogenic process. Thus, there is a great impetus to understand the signals and regulatory pathways that govern the yeast-filament-yeast switch. The majority of studies examining this process, however, have been performed in vitro using conditions that attempt to mimic host-like stimuli. Recent studies in our laboratory have shown that `hyphal defective'mutants `locked'in the yeast mode of growth in vitro are capable of forming filaments during invasion of mucosal tissue in vivo. Additional data suggests that morphogenesis is triggered by host-derived signals at specific tissue sites. Furthermore, these signals activate a morphogenetic pathway that is silent in vitro. Based on these observations, we HYPOTHESIZE that C. albicans possesses a host environment-sensing mechanism that stimulates filamentous growth in response to in vivo mucosal cell contact. In this R21 proposal, we will use emerging technologies to investigate the global transcript profile of C. albicans cells infecting mucosal tissue in vivo and identify genes associated with host-induced morphogenesis. We propose to: 1) identify C. albicans genes expressed during the in vivo host-pathogen interaction;2) identify a subset of C. albicans genes expressed specifically during mucosal-induced morphogenesis;3) validate global expression datasets, and 4) assess the ability of knockout strains to undergo morphogenesis in vitro and in vivo. To our knowledge, this proposal will be the first to: 1) identify the transcriptional signature of C. albicans cells at the in vivo mucosal surface, and 2) elucidate new molecular targets and pathways that are independent of the major in vitro morphological regulators. These studies will generate significant insight into understanding the host-fungal pathogen interaction and allow the development of new antifungal strategies targeting the morphogenetic- and invasive-processes. PUBLIC HEALTH RELEVANCE Our findings will impact current treatment strategies by identifying virulence factors that may be targeted for prophylactic and therapeutic intervention. Such knowledge should accelerate our ability to diagnose, treat, and control the number one fungal pathogen of humans.